ORCID Profile
0000-0003-0346-6837
Current Organisations
University of Western Australia
,
The Harry Perkins Institute of Medical Research
,
University of Gothenburg
,
Goteborgs Universitet
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Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930565.V1
Abstract: b A, /b Kaplan–Meier analysis showing PFS of all patients. b B, /b Kaplan–Meier analysis showing OS of all patients except one. b C, /b Swimmer plot showing time on treatment, time to best response, and duration of response in all patients who received at least one dose of study drug ( i n /i = 29) are shown. b D, /b Kaplan–Meier analysis comparing OS between patients with LDH baseline greater or lower than the upper limit of normal (ULN).
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930547
Abstract: IHC magenta showing low mag of CD20 varied staining of TLS-like (borderline-tertiary lymphoid structures) followed by high magnification images of CD20, CD3, CCL21 within serial sections for Pt 2-027 ( b A /b ), 3-010 ( b B /b ). Also see a href="#SMF5" target="_blank" Supplementary Fig. S5 /a . Low and high magnification images of CD20 sup + /sup TLS-like staining for Pt. 2-026 ( b C /b ) and no TLS s le Pt. 4-017 ( b D /b ). Kaplan–Meier analysis showing PFS ( b E /b ) and OS ( b F /b ), respectively iding patient population into two groups based on IHC, no-TLS ( i n /i = 4) and TLS-like ( i n /i = 18). Also see a href="#SMF5" target="_blank" Supplementary Fig. S5 /a . b G, /b Heatmap showing top 10% genes with highest log sub /sub fold change, among all positively and negatively significantly regulated genes comparing no-TLS and TLS-like groups using bulk RNA-seq (log sub /sub Reads Per Kilobase per Million mapped reads [RPKM] normalized values). Arrows represent relevant TLS-based gene signatures. Genes with FDR-adjusted i P /i values .05 were considered statistically significant. b H, /b In idual box plots showing i CCL19 /i , i CCL21 /i , i CCR7 /i , and i CD79A /i changes in expression between the groups. Statistical tests were carried out using DESeq2 and FDR-adjusted i P /i values were denoted with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5RA02471D
Abstract: The size of functional molecules influences the immobilization efficiency and properties of lipase immobilized on amine-functionalized magnetite–silica nanocomposite particles.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745487.V1
Abstract: Figure S1. a) Time To Response (TTR) according to RECIST 1.1. b) Duration of Response (DOR) according to RECIST 1.1. c) Quality of life assessments: Boxplot of EQ-5D VAS evaluation, screening and last known assessment at database lock. d) EQ-5D VAS, change from screening to last known assessment. e) The functional Assessment of Cancer Therapy – General (FACT-G) score sub-scales at screening and at last known assessments
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745469
Abstract: Representativeness Table
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930559.V1
Abstract: b A, /b Heatmap showing TK1 activity value (DuA) from PEMDAC patient plasma s les, grouped within response groups. Each square is a timepoint for each patient and shows TK1 levels from pretreatment to end of study, until otherwise stated. Total plasma s les analyzed for TK1 = 287. b B, /b Longitudinal TK1 activity for in idual patients, as shown in A. b C /b and b D, /b Kaplan–Meier analysis showing PFS and OS, respectively for pretreatment TK1 values using a threshold of 150 DuA (median TK1 for all s les = 113). Patients with nonavailability of pretreatment s les were excluded from the analysis. b E, /b IHC of TK1 showing nuclear/cytoplasmic magenta staining in patient biopsies 2-027, 3-012, and 3-010. b F, /b Comparison between pretreatment TK1 values for short- and long-term survivors. b G, /b Correlation between pretreatment TK1 (DuA) and circulating tumor DNA (counts/mL) matched patient s les ( i n /i = 21). All statistical tests were unpaired two-tailed i t /i tests, assuming equal variance, with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745466
Abstract: Baseline characteristics, patient population
Publisher: Cold Spring Harbor Laboratory
Date: 10-2002
DOI: 10.1101/GAD.1024602
Abstract: c-Myc promotes cell growth and transformation by ill-defined mechanisms. c- myc −/− mice die by embryonic day 10.5 (E10.5) with defects in growth and in cardiac and neural development. Here we report that the lethality of c- myc −/− embryos is also associated with profound defects in vasculogenesis and primitive erythropoiesis. Furthermore, c- myc −/− embryonic stem (ES) and yolk sac cells are compromised in their differentiative and growth potential. These defects are intrinsic to c-Myc, and are in part associated with a requirement for c-Myc for the expression of vascular endothelial growth factor (VEGF), as VEGF can partially rescue these defects. However, c-Myc is also required for the proper expression of other angiogenic factors in ES and yolk sac cells, including angiopoietin-2, and the angiogenic inhibitors thrombospondin-1 and angiopoietin-1. Finally, c- myc −/− ES cells are dramatically impaired in their ability to form tumors in immune-compromised mice, and the small tumors that sometimes develop are poorly vascularized. Therefore, c-Myc function is also necessary for the angiogenic switch that is indispensable for the progression and metastasis of tumors. These findings support the model wherein c-Myc promotes cell growth and transformation, as well as vascular and hematopoietic development, by functioning as a master regulator of angiogenic factors.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930541
Abstract: Figure S2. a) Gene signatures implicating short term survival. Statistical tests were carried out using DESeq2 and FDR-adjusted P-values were denoted with *, P 0.05 **, P 0.01 ***, P 0.001. b) Average of TK1 values assessed for all timepoints by the number of timepoints ided among response groups, PD, SD, PR. c) TK1 values in different response groups
Publisher: American Association for Cancer Research (AACR)
Date: 15-10-2004
DOI: 10.1158/0008-5472.CAN-04-2133
Abstract: The Eμ-Myc transgenic mouse appears to be an accurate model of human Burkitt’s lymphoma that bears MYC/Immunoglobulin gene translocations. Id2, a negative regulator of basic helix-loop-helix transcription factors, has also been proposed as a Myc target gene that drives the proliferative response of Myc by binding to and overriding the checkpoint functions of the retinoblastoma tumor suppressor protein. Targeted deletion of Id2 in mice results in defects in B-cell development and prevents the development of peripheral lymphoid nodes. In precancerous B cells and lymphomas that arise in Eμ-Myc transgenic mice and in Burkitt’s lymphomas, Id2 is overexpressed, suggesting that it plays a regulatory role in lymphoma development. Surprisingly, despite these connections, Eμ-Myc mice lacking Id2 succumb to lethal B-cell lymphoma at rates comparable with wild-type Eμ-Myc transgenics. Furthermore, precancerous splenic B cells lacking Id2 do not exhibit any significant defects in Myc-induced target gene transactivation and proliferation. However, due to their lack of secondary lymph nodes, Eμ-Myc mice lacking Id2 rather succumb to disseminated lymphoma with an associated leukemia, with pronounced infiltrates of the bone marrow and other major organs. Collectively these findings argue that targeting Id2 functions may be ineffective in preventing Myc-associated malignancies.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930544
Abstract: Figure S1. a) Time To Response (TTR) according to RECIST 1.1. b) Duration of Response (DOR) according to RECIST 1.1. c) Quality of life assessments: Boxplot of EQ-5D VAS evaluation, screening and last known assessment at database lock. d) EQ-5D VAS, change from screening to last known assessment. e) The functional Assessment of Cancer Therapy – General (FACT-G) score sub-scales at screening and at last known assessments
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745463
Abstract: Patient s le information
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745472
Abstract: Figure S6. Analysis of clinical parameters gender (a), tumor BAP1 status (b) and LDH levels (c-d) compared to serum levels of CCL21 (a-c) or presence of TLS-like regions in tumors.
Publisher: Springer Science and Business Media LLC
Date: 10-2018
Publisher: Wiley
Date: 03-05-2011
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930556.V1
Abstract: b A, /b Heatmap of 71 chemokines and cytokines analyzed among all patients and their respective timepoints. Total plasma s les analyzed = 287. Each square represents a timepoint for each patient and shows response group-based levels from pretreatment until end of study, unless otherwise stated. b B, /b Heatmap showing differential pretreatment values between PD and partial responders. Boxed chemokines are significant ( i P /i sub adjusted /sub 0.05) after FDR correction. b C, /b In idual chemokine or cytokine values (pg/mL) compared among different response groups. Only significantly different chemokines from B are included. b D, /b Fold change difference between pretreatment values and week 9 after start of treatment are shown for PD patients. Arrows indicate chemokines that are significant ( i P /i sub adjusted /sub 0.05) after FDR correction between patients that survived longer and those that survived shorter. b E, /b In idual chemokine or cytokine values (pg/mL) compared among different response groups, only significant differences from D are included. Statistical tests in bar charts were unpaired two-tailed i t /i tests (C), assuming unequal variance, or paired i t /i tests (D) with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.COLSURFB.2012.08.044
Abstract: Materials coated with aqueous fish protein extracts can reduce bacterial adhesion, but the mechanism behind the observed effect is not fully understood. In this study we explore the physicochemical properties of fish muscle protein adlayers on four substrates: gold, stainless steel, polystyrene and silicon dioxide. The aims were (i) to determine if the anti-adhesive effect is independent of the underlying substrate chemistry, (ii) to link the physicochemical properties of the adlayer to its ability to repel bacteria, and (iii) to elucidate the mechanism behind this effect. The main proteins on all surfaces were the muscle proteins troponin, tropomyosin, and myosin, and the lipid binding protein apolipoprotein. The quantity, viscoelasticity, and hydration of the protein adlayers varied greatly on the different substrates, but this variation did not affect the bacterial repelling properties. Our results imply that these proteins adsorb to all substrates and provide a steric barrier towards bacterial adhesion, potentially providing a universal antifouling solution.
Publisher: Elsevier BV
Date: 10-2013
Publisher: Informa UK Limited
Date: 04-03-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745478.V1
Abstract: Figure S4. Kaplan–Meier analysis showing PFS of a) CCL13 and b) IL-21. c) Flow cytometry plots showing CCR7 and CD45RA gating among CD3 positive cells in blood s les d) Flow cytometry based comparison between short (n=18) and long (n=6) term survivors with CD3+CCR7+ % (T naive, T stem cell memory and T central memory) analysis using pretreatment blood s les and e) Kaplan–Meier analysis showing Overall survival with median CD3+CCR7+ % (n=24).
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745484.V1
Abstract: Figure S2. a) Gene signatures implicating short term survival. Statistical tests were carried out using DESeq2 and FDR-adjusted P-values were denoted with *, P 0.05 **, P 0.01 ***, P 0.001. b) Average of TK1 values assessed for all timepoints by the number of timepoints ided among response groups, PD, SD, PR. c) TK1 values in different response groups
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-03-2023
DOI: 10.1212/WNL.0000000000201664
Abstract: A causal relationship between statin use and intracerebral hemorrhage (ICH) is uncertain. We hypothesized that an association between long-term statin exposure and ICH risk might vary for different ICH locations. We conducted this analysis using linked Danish nationwide registries. Within the Southern Denmark Region (population 1.2 million), we identified all first-ever cases of ICH between 2009 and 2018 in persons aged ≥55 years. Patients with medical record–verified diagnoses were classified as having a lobar or nonlobar ICH and matched for age, sex, and calendar year to general population controls. We used a nationwide prescription registry to ascertain prior statin and other medication use that we classified for recency, duration, and intensity. Using conditional logistic regression adjusted for potential confounders, we calculated adjusted ORs (aORs) and corresponding 95% CIs for the risk of lobar and nonlobar ICH. We identified 989 patients with lobar ICH (52.2% women, mean age 76.3 years) who we matched to 39,500 controls and 1,175 patients with nonlobar ICH (46.5% women, mean age 75.1 years) who we matched to 46,755 controls. Current statin use was associated with a lower risk of lobar (aOR 0.83 95% CI, 0.70–0.98) and nonlobar ICH (aOR 0.84 95% CI, 0.72–0.98). Longer duration of statin use was also associated with a lower risk of lobar ( year: aOR 0.89 95% CI, 0.69–1.14 ≥1 year to years aOR 0.89 95% CI 0.73–1.09 ≥5 years aOR 0.67 95% CI, 0.51–0.87 p for trend 0.040) and nonlobar ICH ( year: aOR 1.00 95% CI, 0.80–1.25 ≥1 year to years aOR 0.88 95% CI 0.73–1.06 ≥5 years aOR 0.62 95% CI, 0.48–0.80 p for trend .001). Estimates stratified by statin intensity were similar to the main estimates for low-medium intensity therapy (lobar aOR 0.82 nonlobar aOR 0.84) the association with high-intensity therapy was neutral. We found that statin use was associated with a lower risk of ICH, particularly with longer treatment duration. This association did not vary by hematoma location.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930562.V1
Abstract: b A /b and b B, /b Kaplan–Meier analysis showing PFS and OS of patients with a wildtype i BAP1 /i status and UV-damaged uveal melanoma genome. PFS ( b C /b ) and OS ( b D /b ) analyses comparing patients with GNAQ- or GNA11-mutated uveal melanoma. b E, /b Volcano plot showing differentially expressed genes between short term ( i n /i = 16) and long term (alive patients, i n /i = 4) from bulk RNA-seq. Genes with FDR-adjusted i P /i values .05 were considered statistically significant. b F, /b In idual box plots showing relevant gene signatures implicating long-term (alive patients) survival. Statistical tests were carried out using DESeq2 and FDR-adjusted i P /i values were denoted with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: American Association for Cancer Research (AACR)
Date: 31-08-2017
DOI: 10.1158/0008-5472.CAN-16-3172
Abstract: Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell–based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were lified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNγ signaling, led to impaired recognition by tumor-specific CD8+ T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I–related APM. Loss of target antigens or impaired IFNγ signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each in idual patient are warranted. Cancer Res 77(17) 4562–6. ©2017 AACR.
Publisher: Informa UK Limited
Date: 2019
DOI: 10.1080/02656736.2019.1601778
Abstract: Isolated limb perfusion (ILP) is a treatment option for unresectable in-transit melanoma metastases of the extremities. Approximately two-thirds of the patients have a complete response, and known predictive factors mainly regard tumor burden. In an attempt to identify subgroups with higher response rates, we retrospectively analyzed the predictive value of the BRAF V600E/K mutation for response at our institution. Between January 2012 and December 2017, 98 consecutive patients underwent first-time ILP with melphalan for melanoma in-transit metastases and were included in the study. Data was retrieved from our prospectively kept database. Tumor burden was assessed preoperatively as number of lesions and largest tumor diameter. BRAF status was determined according to clinical routine. Response rates were classified according to WHO criteria. Of the 98 patients included in the analysis, 32 patients had a BRAF V600E/K mutation (33%) and 66 patients were BRAF wild type (wt). There was no difference in age, sex or tumor burden between the groups. Comparing response between BRAF V600E/K mutation and BRAF wt, the overall response rate was 69% vs. 77% (p=.36) and the complete response rate was 47% vs. 52% (p=.67). There was no difference in survival, with a median survival of 47 months. In this consecutive series of patients, BRAF V600E/K mutation was not found to be a significant factor for response or survival following ILP.
Publisher: Proceedings of the National Academy of Sciences
Date: 16-11-2016
Abstract: Structural changes in chromosomes can alter the expression and function of genes in tumors, an important driving mechanism in some tumors. Whole-genome sequencing makes it possible to detect such events on a genome-wide scale, but comprehensive investigations are still missing. Here, enabled by a massive amount of whole-genome sequencing data generated by The Cancer Genome Atlas consortium, we map somatic structural changes in 600 tumors of erse origins. At a global level, we find that such events often contribute to altered gene expression in human cancer, and also highlight specific events that may have functional roles during tumor development.
Publisher: Elsevier BV
Date: 2022
Publisher: Springer Science and Business Media LLC
Date: 13-11-2006
Abstract: p18(Ink4c) functions as a dedicated inhibitor of cyclin-D-dependent kinases. Loss of Ink4c predisposes mice to tumor development and, in a dose-dependent manner, complements the tumor-promoting effects of various oncogenes. We have now addressed whether Ink4c loss impacts B-cell tumor development in the Emu-Myc transgenic mouse, a model of human Burkitt lymphoma. Loss of one or both alleles did not influence the onset of lymphoma in Emu-Myc transgenics, and did not appreciably affect Myc's proliferative or apoptotic responses in precancerous B cells. Nevertheless, Ink4c loss modulated the effects of Myc-induced transformation by decreasing the frequency of Arf loss, an ordinarily common event in Emu-Myc-induced lymphomas.
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2JM30513E
Publisher: Cambridge University Press
Date: 04-01-2007
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0SM01360A
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930535
Abstract: Figure S4. Kaplan–Meier analysis showing PFS of a) CCL13 and b) IL-21. c) Flow cytometry plots showing CCR7 and CD45RA gating among CD3 positive cells in blood s les d) Flow cytometry based comparison between short (n=18) and long (n=6) term survivors with CD3+CCR7+ % (T naive, T stem cell memory and T central memory) analysis using pretreatment blood s les and e) Kaplan–Meier analysis showing Overall survival with median CD3+CCR7+ % (n=24).
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930538
Abstract: Figure S3. a) Heat map showing plasma chemokine and cytokine levels pre-treatment to end of study (EOS) in patients with progressive disease (PD) b) Heat map of plasma chemokine levels pre-treatment to EOS in stable disease (SD) patients. c) Heat map of plasma chemokine levels pre-treatment to EOS in partial response (PR) patients d) Levels of CXCL9 in different response groups pretreatment and EOS. e) Levels of CXCL9 pretreatment and EOS in patients surviving longer or shorter in the PEMDAC trail.
Publisher: Wiley
Date: 26-07-2006
DOI: 10.1111/J.1471-4159.2006.04104.X
Abstract: Compounds blocking the uptake of the endogenous cannabinoid anandamide (AEA) have been used to explore the functions of the endogenous cannabinoid system in the CNS both in vivo and in vitro . In this study, the effects of four commonly used acyl‐based uptake inhibitors [ N ‐(4‐hydroxyphenyl)arachidonylamide (AM404), N ‐(4‐hydroxy‐2‐methylphenyl) arachidonoyl amide (VDM11), (5 Z ,8 Z ,11 Z ,14 Z )‐ N ‐(3‐furanylmethyl)‐5,8,11,14‐eicosatetraenamide (UCM707) and (9 Z )‐ N ‐[1‐(( R )‐4‐hydroxybenzyl)‐2‐hydroxyethyl]‐9‐octadecen‐amide (OMDM2)] and the related compound arvanil on C6 glioma cell viability were investigated. All five compounds reduced the ability of the cells to accumulate calcein, reduced the total nucleic acid content and increased the activity of lactate dehydrogenase recovered in the cell medium. AM404 (10 µ m ) and VDM11 (10 µ m ) acted rapidly, reducing cell viability after 3 h of exposure when cell densities of 5000 per well were used. In contrast, UCM707 (30 µ m ), OMDM2 (10 µ m ) and the related compound arvanil (10 µ m ) produced a more slowly developing effect on cell viability, although robust effects were seen after 6–9 h of exposure. At higher cell densities, the toxicities of AM404 and UCM707 were reduced. Comparison of the compounds with arachidonic acid, arachidonic acid methyl ester, AEA, arachidonoyl glycine and oleic acid suggested that the toxicity of the arachidonoyl‐based compounds was related primarily to the acyl side‐chain rather than the head group. A variety of pre‐treatments blocking possible metabolic pathways and receptor targets were tested, but the only consistent protective treatment against the effects of these compounds was the antioxidant N ‐acetyl‐ l ‐cysteine. It is concluded that AM404, VDM11, UCM707 and OMDM2 produce a rapid loss of C6 glioma cell viability over the same concentration range as is required for the inhibition of AEA uptake in vitro , albeit with a longer latency. Such effects should be kept in mind when acyl‐derived compounds are used to probe the function of the endocannabinoid system in the CNS, particularly in chronic administration protocols.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745478
Abstract: Figure S4. Kaplan–Meier analysis showing PFS of a) CCL13 and b) IL-21. c) Flow cytometry plots showing CCR7 and CD45RA gating among CD3 positive cells in blood s les d) Flow cytometry based comparison between short (n=18) and long (n=6) term survivors with CD3+CCR7+ % (T naive, T stem cell memory and T central memory) analysis using pretreatment blood s les and e) Kaplan–Meier analysis showing Overall survival with median CD3+CCR7+ % (n=24).
Publisher: American Association for the Advancement of Science (AAAS)
Date: 29-01-2014
DOI: 10.1126/SCITRANSLMED.3007653
Abstract: The antioxidants acetylcysteine and vitamin E accelerate tumor progression and reduce survival in mouse models of lung cancer by disrupting the ROS-p53 axis.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745475
Abstract: Figure S5. Immunohistochemistry magenta of a) Immunohistochemistry magenta showing CCL21 and corresponding CCR7 expression within tumor biopsies for patient 1-013 and 3-009. b) Patient 1-013, a lymph node biopsy showing CD20, CD3 and CCL21 staining with serial sections. c) Patient 2-027, a liver met biopsy showing SOX10, CCR7, TK1 and PDL1 (DAB) within the same areas as shown in Fig 6.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930532
Abstract: Figure S5. Immunohistochemistry magenta of a) Immunohistochemistry magenta showing CCL21 and corresponding CCR7 expression within tumor biopsies for patient 1-013 and 3-009. b) Patient 1-013, a lymph node biopsy showing CD20, CD3 and CCL21 staining with serial sections. c) Patient 2-027, a liver met biopsy showing SOX10, CCR7, TK1 and PDL1 (DAB) within the same areas as shown in Fig 6.
Publisher: American Society of Hematology
Date: 02-09-2010
DOI: 10.1182/BLOOD-2009-11-251074
Abstract: Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.IMMUNI.2015.01.012
Abstract: Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient s les and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and lified response to microbial and environmental threats.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745481
Abstract: Figure S3. a) Heat map showing plasma chemokine and cytokine levels pre-treatment to end of study (EOS) in patients with progressive disease (PD) b) Heat map of plasma chemokine levels pre-treatment to EOS in stable disease (SD) patients. c) Heat map of plasma chemokine levels pre-treatment to EOS in partial response (PR) patients d) Levels of CXCL9 in different response groups pretreatment and EOS. e) Levels of CXCL9 pretreatment and EOS in patients surviving longer or shorter in the PEMDAC trail.
Publisher: Springer Science and Business Media LLC
Date: 28-10-2021
Publisher: Springer Science and Business Media LLC
Date: 12-2015
DOI: 10.1245/S10434-015-4982-5
Abstract: This report describes the outcomes and long-term follow-up data from all isolated hepatic perfusions (IHPs) performed at a single institution in Sweden between the years 1989 and 2013 for patients with isolated uveal melanoma metastases. A total of 68 patients (median age, 61 years) were treated consecutively at Sahlgrenska University Hospital. Of the 68 patients, 67 % had fewer than 10 tumors. The median diameter of the largest lesion was 2.5 cm. The patients underwent IHP with either melphalan alone or the addition of either tumor necrosis factor-alpha or cisplatin. The response was assessed after 8-12 weeks by computed tomography or magnetic resonance imaging. The overall response rate was 67 and 20 % of the patients had a complete response. The median times to local and systemic progression were respectively 10 and 14 months. The prognostic factors for time to local recurrence were response and number of tumors. The median survival time was 22 months. The prognostic factors for survival were response, largest tumor diameter, and number of tumors. Five patients (7 %) died within 30 days, and six patients (9 %) experienced major complications (Clavien-Dindo 3/4). Isolated hepatic perfusion is a treatment option with high response rates and tolerable mortality and morbidity. Whether IHP has a survival benefit compared with other treatment options currently is being investigated in a randomized trial.
Publisher: MDPI AG
Date: 20-01-2023
Abstract: Patients with metastatic melanoma have a historically poor prognosis, but recent advances in treatment options, including targeted therapy and immunotherapy, have drastically improved the outcomes for some of these patients. However, not all patients respond to available treatments, and around 50% of patients with metastatic cutaneous melanoma and almost all patients with metastases of uveal melanoma die of their disease. Thus, there is a need for novel treatment strategies for patients with melanoma that do not benefit from the available therapies. Chimeric antigen receptor-expressing T (CAR-T) cells are largely unexplored in melanoma. Traditionally, CAR-T cells have been produced by transducing blood-derived T cells with a virus expressing CAR. However, tumor-infiltrating lymphocytes (TILs) can also be engineered to express CAR, and such CAR-TILs could be dual-targeting. To this end, tumor s les and autologous TILs from metastasized human uveal and cutaneous melanoma were expanded in vitro and transduced with a lentiviral vector encoding an anti-HER2 CAR construct. When infused into patient-derived xenograft (PDX) mouse models carrying autologous tumors, CAR-TILs were able to eradicate melanoma, even in the absence of antigen presentation by HLA. To advance this concept to the clinic and assess its safety in an immune-competent and human-patient-like setting, we treated four companion dogs with autologous anti-HER2 CAR-TILs. We found that these cells were tolerable and showed signs of anti-tumor activity. Taken together, CAR-TIL therapy is a promising avenue for broadening the tumor-targeting capacity of TILs in patients with checkpoint immunotherapy-resistant melanoma.
Publisher: Oxford University Press (OUP)
Date: 12-12-2017
DOI: 10.1093/BRAIN/AWW314
Abstract: Ischaemic stroke induces endogenous repair processes that include proliferation and differentiation of neural stem cells and extensive rewiring of the remaining neural connections, yet about 50% of stroke survivors live with severe long-term disability. There is an unmet need for drug therapies to improve recovery by promoting brain plasticity in the subacute to chronic phase after ischaemic stroke. We previously showed that complement-derived peptide C3a regulates neural progenitor cell migration and differentiation in vitro and that C3a receptor signalling stimulates neurogenesis in unchallenged adult mice. To determine the role of C3a-C3a receptor signalling in ischaemia-induced neural plasticity, we subjected C3a receptor-deficient mice, GFAP-C3a transgenic mice expressing biologically active C3a in the central nervous system, and their respective wild-type controls to photothrombotic stroke. We found that C3a overexpression increased, whereas C3a receptor deficiency decreased post-stroke expression of GAP43 (P < 0.01), a marker of axonal sprouting and plasticity, in the peri-infarct cortex. To verify the translational potential of these findings, we used a pharmacological approach. Daily intranasal treatment of wild-type mice with C3a beginning 7 days after stroke induction robustly increased synaptic density (P < 0.01) and expression of GAP43 in peri-infarct cortex (P < 0.05). Importantly, the C3a treatment led to faster and more complete recovery of forepaw motor function (P < 0.05). We conclude that C3a-C3a receptor signalling stimulates post-ischaemic neural plasticity and intranasal treatment with C3a receptor agonists is an attractive approach to improve functional recovery after ischaemic brain injury.
Publisher: Informa UK Limited
Date: 30-06-2020
Publisher: Wiley
Date: 20-09-2019
Publisher: Medical Journals Sweden AB
Date: 24-01-2019
Publisher: American Chemical Society (ACS)
Date: 06-05-2011
DOI: 10.1021/NN102867Z
Abstract: We demonstrate the use of binary colloidal assemblies as lithographic masks to generate tunable Au patterns on SiO(2) substrates with dimensions ranging from micrometers to nanometers. Such patterns can be modified with different chemistries to create patterns with well-defined sites for selective adsorption of proteins, where the pattern size and spacing is adjustable depending on particle choice. In our system, the binary colloidal assemblies contain large and small particles of similar or different material and are self-assembled from dilute dispersions with particle size ratios ranging from 0.10 to 0.50. This allows masks with variable morphology and thus production of chemical patterns of tunable geometry. Finally, the Au or SiO(2) regions of the pattern are surface modified with protein resistant oligoethyleneglycol self-assembled molecules, which facilitates site selective adsorption of proteins into the unmodified regions of the pattern. This we show with fluorescently labeled bovine serum albumin.
Publisher: Oxford University Press (OUP)
Date: 04-2009
DOI: 10.1111/J.1365-2672.2008.04090.X
Abstract: Preconditioning of stainless steel with aqueous cod muscle extract significantly impedes subsequent bacterial adhesion most likely due to repelling effects of fish tropomyosin. The purpose of this study was to determine if other food conditioning films decrease or enhance bacterial adhesion to stainless steel. Attachment of Pseudomonas fluorescens AH2 to stainless steel coated with water-soluble coatings of animal origin was significantly reduced as compared with noncoated stainless steel or stainless steel coated with laboratory substrate or extracts of plant origin. Coating with animal extracts also decreases adhesion of other food-relevant bacteria. The manipulation of adhesion was not attributable to growth inhibitory effects. Chemical analysis revealed that the stainless steels were covered by homogenous layers of adsorbed proteins. The presence of tropomyocin was indicated by appearance of proteins with similar molecular weight based in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, in several extracts that reduced adhesion but also extracts not containing this protein reduced bacterial adhesion, indicating that several molecular species may be involved in the phenomenon. It is a common perception that food materials facilitate bacterial adhesion to surfaces however, this study demonstrates that aqueous coatings of food origin may actually reduce bacterial adhesion. Compounds from food extracts may potentially be used as nontoxic coatings to reduce bacterial attachment to inert surfaces.
Publisher: MDPI AG
Date: 02-11-2020
Abstract: Previous studies have demonstrated an anti-tumoral effect of beta-adrenergic blocking agents on cutaneous melanoma (CM). The aim of this study was to investigate if beta-adrenergic blocking agents have an impact on survival in Swedish patients with melanoma. A population-based retrospective registry study including all patients diagnosed with a primary invasive melanoma between 2009 and 2013 was performed. Data from the Swedish Melanoma Register were linked to the Swedish Prescribed Drug Registry and the Swedish Cause of Death Register. Cox regression analyses including competing risk assessments were performed. There were 12,738 patients included, out of which 3702 were exposed to beta-blockers vs. 9036 non-exposed patients. Age, male sex, Breslow thickness, ulceration, and nodal status were independent negative prognostic factors for melanoma-specific survival (MSS). Adding beta-blockers to the analysis did not add any prognostic value to the model (HR 1.00, p = 0.98), neither when adjusting for competing risks (HR 0.97, p = 0.61). When specifically analyzing the use of non-selective beta-blockers, the results were still without statistical significance (HR 0.76, p = 0.21). In conclusion, this population-based registry study could not verify that the use of beta-adrenergic blocking agents improve survival in patients with melanoma.
Publisher: Informa UK Limited
Date: 10-2003
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745472.V1
Abstract: Figure S6. Analysis of clinical parameters gender (a), tumor BAP1 status (b) and LDH levels (c-d) compared to serum levels of CCL21 (a-c) or presence of TLS-like regions in tumors.
Publisher: American Society of Hematology
Date: 30-04-2009
DOI: 10.1182/BLOOD-2008-10-183475
Abstract: Decitabine (also referred to as 5-aza-2′-deoxycytidine) is a drug that has recently been approved by the Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome (MDS). The mechanism of action is believed to be the blocking of DNA methylation and thereby reactivating silenced genes involved in harnessing MDS. When analyzing reactivation of genes involved in Burkitt lymphoma (BL), we discovered that decitabine also sensitizes tumor cells by inducing DNA damage. This sensitization is grossly augmented by the MYC oncogene, which is overexpressed in BL, and occurs in cells lacking a functional p53 tumor suppressor pathway. In p53-deficient BL cells and p53−/− mouse embryo fibroblasts, Myc overrides a transient G2-block exerted by decitabine via activation of Chk1. This triggers aneuploidy and cell death that correlates with, but can occur in the absence of, Epstein-Barr virus (EBV) reactivation, caspase activation, and/or expression of the BH3-only protein Puma. In vivo modeling of Myc-induced lymphoma suggests that decitabine constitutes a potential new drug against lymphoma that would selectively sensitize tumor cells but spare normal tissue.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745466.V1
Abstract: Baseline characteristics, patient population
Publisher: Proceedings of the National Academy of Sciences
Date: 16-06-2014
Abstract: Bromodomain and extraterminal (BET) proteins bind acetylated proteins, including histones, and regulate transcription. Interestingly, inhibitors of BET proteins (BETi) can block cancer cell proliferation and induce apoptosis in a wide range of tumor types. To date many of the effects of BETi have been attributed to transcriptional suppression of genes like the MYC oncogene. We show that genetically-engineered Myc-induced lymphoma mouse models are highly sensitive to BETi without MYC transcription being suppressed. Our data suggest broad effects on transcription by BETi including a set of genes being induced. Here a genetic and functional link between BET proteins and histone deacetylases is unraveled that opens up avenues for combination therapies against cancer.
Publisher: Springer Science and Business Media LLC
Date: 02-05-2019
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2016
DOI: 10.1158/0008-5472.CAN-15-2721
Abstract: Agents that trigger cell differentiation are highly efficacious in treating certain cancers, but such approaches are not generally effective in most malignancies. Compounds such as DMSO and hexamethylene bisacetamide (HMBA) have been used to induce differentiation in experimental systems, but their mechanisms of action and potential range of uses on that basis have not been developed. Here, we show that HMBA, a compound first tested in the oncology clinic over 25 years ago, acts as a selective bromodomain inhibitor. Biochemical and structural studies revealed an affinity of HMBA for the second bromodomain of BET proteins. Accordingly, both HMBA and the prototype BET inhibitor JQ1 induced differentiation of mouse erythroleukemia cells. As expected of a BET inhibitor, HMBA displaced BET proteins from chromatin, caused massive transcriptional changes, and triggered cell-cycle arrest and apoptosis in Myc-induced B-cell lymphoma cells. Furthermore, HMBA exerted anticancer effects in vivo in mouse models of Myc-driven B-cell lymphoma. This study illuminates the function of an early anticancer agent and suggests an intersection with ongoing clinical trials of BET inhibitor, with several implications for predicting patient selection and response rates to this therapy and starting points for generating BD2-selective BET inhibitors. Cancer Res 76(8) 2376–83. ©2016 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930538.V1
Abstract: Figure S3. a) Heat map showing plasma chemokine and cytokine levels pre-treatment to end of study (EOS) in patients with progressive disease (PD) b) Heat map of plasma chemokine levels pre-treatment to EOS in stable disease (SD) patients. c) Heat map of plasma chemokine levels pre-treatment to EOS in partial response (PR) patients d) Levels of CXCL9 in different response groups pretreatment and EOS. e) Levels of CXCL9 pretreatment and EOS in patients surviving longer or shorter in the PEMDAC trail.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930562
Abstract: b A /b and b B, /b Kaplan–Meier analysis showing PFS and OS of patients with a wildtype i BAP1 /i status and UV-damaged uveal melanoma genome. PFS ( b C /b ) and OS ( b D /b ) analyses comparing patients with GNAQ- or GNA11-mutated uveal melanoma. b E, /b Volcano plot showing differentially expressed genes between short term ( i n /i = 16) and long term (alive patients, i n /i = 4) from bulk RNA-seq. Genes with FDR-adjusted i P /i values .05 were considered statistically significant. b F, /b In idual box plots showing relevant gene signatures implicating long-term (alive patients) survival. Statistical tests were carried out using DESeq2 and FDR-adjusted i P /i values were denoted with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930565
Abstract: b A, /b Kaplan–Meier analysis showing PFS of all patients. b B, /b Kaplan–Meier analysis showing OS of all patients except one. b C, /b Swimmer plot showing time on treatment, time to best response, and duration of response in all patients who received at least one dose of study drug ( i n /i = 29) are shown. b D, /b Kaplan–Meier analysis comparing OS between patients with LDH baseline greater or lower than the upper limit of normal (ULN).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-11-2021
Publisher: Springer Science and Business Media LLC
Date: 12-05-2011
DOI: 10.1007/S10495-011-0606-0
Abstract: Type I interferons constitute a family of pleiotropic cytokines that have a key role in both adaptive and innate immunity. The interferon signalling pathways mediate transcriptional regulation of hundreds of genes, which result in mRNA degradation, decreased protein synthesis, cell cycle inhibition and induction of apoptosis. To elucidate regulatory networks important for interferon induced cell death, we generated interferon resistant U937 cells by selection in progressively increasing concentrations of interferon-α (IFN-α). The results show that IFN-α activates the death receptor signalling pathway and that IFN resistance was associated with cross-resistance to several death receptor ligands in a manner similar to previously described Fas resistant U937 cell lines. Increased expression of the long splice variant of the cellular FLICE-like inhibitor protein (cFLIP-L) was associated with the resistance to death receptor and IFN-α stimulation. Accordingly, inhibition of cFLIP-L expression with cycloheximide or through cFLIP short harpin RNA interference restored sensitivity to Fas and/or IFN-α. Thus, we now show that selection for interferon resistance can generate cells with increased expression of cFLIP, which protects the cells from both IFN-α and death receptor mediated apoptosis.
Publisher: Springer Science and Business Media LLC
Date: 02-07-2010
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930535.V1
Abstract: Figure S4. Kaplan–Meier analysis showing PFS of a) CCL13 and b) IL-21. c) Flow cytometry plots showing CCR7 and CD45RA gating among CD3 positive cells in blood s les d) Flow cytometry based comparison between short (n=18) and long (n=6) term survivors with CD3+CCR7+ % (T naive, T stem cell memory and T central memory) analysis using pretreatment blood s les and e) Kaplan–Meier analysis showing Overall survival with median CD3+CCR7+ % (n=24).
Publisher: American Association for Cancer Research (AACR)
Date: 02-2010
DOI: 10.1158/1940-6207.CAPR-09-0166
Abstract: The oncogenic transcription factor c-Myc (Myc) is frequently overexpressed in human cancers. Myc is known to induce or repress a large set of genes involved in cell growth and proliferation, explaining the selection for mutations in cancer that deregulate Myc expression. Inhibition of ornithine decarboxylase, an enzyme of the polyamine biosynthetic pathway and a Myc target, has been shown to be chemopreventive. In the present study, we have dissected the role of another enzyme in the polyamine biosynthetic pathway, spermidine synthase (Srm), in Myc-induced cancer. We find that Srm is encoded by a Myc target gene containing perfect E-boxes and that it is induced by Myc in a direct manner. RNA interference against Srm shows that it is important for Myc-induced proliferation of mouse fibroblasts but to a lesser extent for transformation. Using the compound trans-4-methylcyclohexylamine, we show that Srm inhibition can delay the onset of B-cell lymphoma development in λ-Myc transgenic mice. We therefore suggest that inhibition of Srm is an additional chemopreventive strategy that warrants further consideration. Cancer Prev Res 3(2) 140–7
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2018
DOI: 10.1200/PO.18.00002
Abstract: Cancer of unknown primary is a group of metastatic tumors in which the standard diagnostic workup fails to identify the site of origin of the tumor. The potential impact of precision oncology on this group of patients is large, because actionable driver mutations and a correct diagnosis could provide treatment options otherwise not available for patients with these fatal cancers. This study investigated if comprehensive genomic analyses could provide information on the origin of the tumor. Here we describe a patient whose tumor was misdiagnosed at least three times. Next-generation sequencing, a patient-derived xenograft mouse model, and bioinformatics were used to identify an actionable mutation, predict resistance development to the targeted therapy, and correctly diagnose the origin of the tumor. Transcriptomic classification was benchmarked using The Cancer Genome Atlas (TCGA). Despite the lack of a known primary tumor site and the absence of diagnostic immunohistochemical markers, the origin of the patient’s tumor was established using the novel bioinformatic workflow. This included a mutational signature analysis of the sequenced metastases and comparison of their transcriptomic profiles to a pan-cancer panel of tumors from TCGA. We further discuss the strengths and limitations of the latter approaches in the context of three potentially incorrectly diagnosed TCGA lung tumors. Comprehensive genomic analyses can provide information on the origin of tumors in patients with cancer of unknown primary.
Publisher: Springer Science and Business Media LLC
Date: 24-07-2018
DOI: 10.1038/S41419-018-0865-6
Abstract: Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could ide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1 , which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not h er T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930556
Abstract: b A, /b Heatmap of 71 chemokines and cytokines analyzed among all patients and their respective timepoints. Total plasma s les analyzed = 287. Each square represents a timepoint for each patient and shows response group-based levels from pretreatment until end of study, unless otherwise stated. b B, /b Heatmap showing differential pretreatment values between PD and partial responders. Boxed chemokines are significant ( i P /i sub adjusted /sub 0.05) after FDR correction. b C, /b In idual chemokine or cytokine values (pg/mL) compared among different response groups. Only significantly different chemokines from B are included. b D, /b Fold change difference between pretreatment values and week 9 after start of treatment are shown for PD patients. Arrows indicate chemokines that are significant ( i P /i sub adjusted /sub 0.05) after FDR correction between patients that survived longer and those that survived shorter. b E, /b In idual chemokine or cytokine values (pg/mL) compared among different response groups, only significant differences from D are included. Statistical tests in bar charts were unpaired two-tailed i t /i tests (C), assuming unequal variance, or paired i t /i tests (D) with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: MDPI AG
Date: 30-12-2020
Abstract: We thank De Giorgi et al for their interest in our study, and for raising important and relevant questions [...]
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930559
Abstract: b A, /b Heatmap showing TK1 activity value (DuA) from PEMDAC patient plasma s les, grouped within response groups. Each square is a timepoint for each patient and shows TK1 levels from pretreatment to end of study, until otherwise stated. Total plasma s les analyzed for TK1 = 287. b B, /b Longitudinal TK1 activity for in idual patients, as shown in A. b C /b and b D, /b Kaplan–Meier analysis showing PFS and OS, respectively for pretreatment TK1 values using a threshold of 150 DuA (median TK1 for all s les = 113). Patients with nonavailability of pretreatment s les were excluded from the analysis. b E, /b IHC of TK1 showing nuclear/cytoplasmic magenta staining in patient biopsies 2-027, 3-012, and 3-010. b F, /b Comparison between pretreatment TK1 values for short- and long-term survivors. b G, /b Correlation between pretreatment TK1 (DuA) and circulating tumor DNA (counts/mL) matched patient s les ( i n /i = 21). All statistical tests were unpaired two-tailed i t /i tests, assuming equal variance, with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745469.V1
Abstract: Representativeness Table
Publisher: Informa UK Limited
Date: 08-2018
DOI: 10.2147/CLEP.S167576
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5RA08405A
Abstract: Surface chemistry/charge and concentration of mesoporous silica nanoparticles have a great impact on the fibrillation process of α-Syn protein.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745457
Abstract: Complete differential expression results
Publisher: Springer Science and Business Media LLC
Date: 17-07-2017
DOI: 10.1038/NM.4369
Publisher: Wiley
Date: 26-04-2007
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930553
Abstract: Kaplan–Meier analysis showing. PFS ( b A /b ) and OS ( b B /b ), respectively using pretreatment plasma CCL21 (pg/mL) measurements based on their median values. b C, /b Correlation between CCL21 (pg/mL) and CD3 sup + /sup CCR7 sup + /sup CD45RA sup + /sup (% counts) matched patient s les ( i n /i = 23). b D, /b Flow cytometry–based comparison between short- and long-term survivors for CD3 sup + /sup CCR7 sup + /sup CD45RA sup + /sup % (T naïve and T stem cell memory) analysis using pretreatment blood s les ( i n /i = 24). Statistical test was unpaired two-tailed i t /i tests, assuming equal variance. b E, /b Kaplan–Meier analysis showing OS using median CD3 sup + /sup CCR7 sup + /sup CD45RA sup + /sup % values.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745454
Abstract: GSEA
Publisher: Informa UK Limited
Date: 03-2005
Publisher: Springer Science and Business Media LLC
Date: 09-08-2014
Publisher: Cold Spring Harbor Laboratory
Date: 21-01-2020
DOI: 10.1101/2020.01.21.913467
Abstract: Chk1 kinase is downstream of the ATR kinase in the sensing of improper replication. Previous cell culture studies have demonstrated that Chk1 is essential for replication and Chk1 inhibitors are efficacious against tumors with high-level replication stress such as Myc-induced lymphoma cells. Treatment with Chk1 inhibitors also combines well with certain chemotherapeutic drugs and effects associates with induction of DNA damage and reduction of Chk1 protein levels. Most studies of Chk1 function has relied on the use of inhibitors. Whether or not a mouse or cancer cells could survive if a kinase-dead form of Chk1 is expressed has not been investigated before. Here we generate a mouse model that expresses a kinase-dead (D130A) allele in the mouse germline. We find that this mouse is overtly normal and does not have problems with erythropoiesis with ageing as previously been shown for a mouse expressing one null allele. However, similar to a null allele, homozygous kinase-dead mice cannot be generated and timed pregnancies of heterozygous mice suggest lethality of homozygous blastocysts at around the time of implantation. By breeding the kinase-dead Chk1 mouse with a conditional allele we are able to demonstrate that expression of only one kinase-dead allele, but no wildtype allele, of Chek1 is lethal for Myc-induced cancer cells. Finally, treatment of melanoma cells with tumor-infiltrating T cells or CAR-T cells is effective even if Chk1 is inhibited, suggesting that Chk1 inhibitors can be safely administered in patients where immunotherapy is an essential component of the arsenal against cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930529.V1
Abstract: Figure S6. Analysis of clinical parameters gender (a), tumor BAP1 status (b) and LDH levels (c-d) compared to serum levels of CCL21 (a-c) or presence of TLS-like regions in tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745481.V1
Abstract: Figure S3. a) Heat map showing plasma chemokine and cytokine levels pre-treatment to end of study (EOS) in patients with progressive disease (PD) b) Heat map of plasma chemokine levels pre-treatment to EOS in stable disease (SD) patients. c) Heat map of plasma chemokine levels pre-treatment to EOS in partial response (PR) patients d) Levels of CXCL9 in different response groups pretreatment and EOS. e) Levels of CXCL9 pretreatment and EOS in patients surviving longer or shorter in the PEMDAC trail.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745460
Abstract: Follow up adverse events (AE) of grade ≥3 (n = 29 patients)
Publisher: American Association for Cancer Research (AACR)
Date: 03-2019
DOI: 10.1158/0008-5472.CAN-18-3158
Abstract: These findings demonstrate that a novel humanized mouse model can help clinical translation of CAR-T cells against uveal and cutaneous melanoma that do not respond to TIL therapy or immune checkpoint blockade.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2014
DOI: 10.1038/NG.3141
Abstract: Somatic mutations in noncoding sequences are poorly explored in cancer, a rare exception being the recent identification of activating mutations in TERT regulatory DNA. Although this finding is suggestive of a general mechanism for oncogene activation, this hypothesis remains untested. Here we map somatic mutations in 505 tumor genomes across 14 cancer types and systematically screen for associations between mutations in regulatory regions and RNA-level changes. We identify recurrent promoter mutations in several genes but find that TERT mutations are exceptional in showing a strong and genome-wide significant association with increased expression. Detailed analysis of TERT across cancers shows that the strength of this association is highly variable and is strongest in copy number-stable cancers such as thyroid carcinoma. We additionally propose that TERT promoter mutations control expression of the nearby gene CLPTM1L. Our analysis provides a detailed pan-cancer view of TERT transcriptional activation but finds no clear evidence for frequent oncogenic promoter mutations beyond TERT.
Publisher: Public Library of Science (PLoS)
Date: 15-03-2012
Publisher: Elsevier BV
Date: 06-2013
Publisher: Springer Science and Business Media LLC
Date: 27-09-2017
DOI: 10.1038/S41467-017-00786-Z
Abstract: Immune checkpoint inhibitors and adoptive cell transfer (ACT) of autologous tumor-infiltrating T cells have shown durable responses in patients with melanoma. To study ACT and immunotherapies in a humanized model, we have developed PDXv2.0 — a melanoma PDX model where tumor cells and tumor-infiltrating T cells from the same patient are transplanted sequentially in non-obese diabetic/severe combined immune-deficient/common gamma chain (NOG/NSG) knockout mouse. Key to T-cell survival/effect in this model is the continuous presence of interleukin-2 (IL-2). Tumors that grow in PDXv2.0 are eradicated if the autologous tumor cells and T cells come from a patient that exhibited an objective response to ACT in the clinic. However, T cells from patients that are non-responders to ACT cannot kill tumor cells in PDXv2.0. Taken together, PDXv2.0 provides the potential framework to further model genetically erse human cancers for assessing the efficacy of immunotherapies as well as combination therapies.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745475.V1
Abstract: Figure S5. Immunohistochemistry magenta of a) Immunohistochemistry magenta showing CCL21 and corresponding CCR7 expression within tumor biopsies for patient 1-013 and 3-009. b) Patient 1-013, a lymph node biopsy showing CD20, CD3 and CCL21 staining with serial sections. c) Patient 2-027, a liver met biopsy showing SOX10, CCR7, TK1 and PDL1 (DAB) within the same areas as shown in Fig 6.
Publisher: American Chemical Society (ACS)
Date: 04-09-2013
DOI: 10.1021/NN402232G
Abstract: Exosomes, the endogenous nanocarriers that can deliver biological information between cells, were recently introduced as new kind of drug delivery system. However, mammalian cells release relatively low quantities of exosomes, and purification of exosomes is difficult. Here, we developed bioinspired exosome-mimetic nanovesicles that deliver chemotherapeutics to the tumor tissue after systemic administration. The chemotherapeutics-loaded nanovesicles were produced by the breakdown of monocytes or macrophages using a serial extrusion through filters with diminishing pore sizes (10, 5, and 1 μm). These cell-derived nanovesicles have similar characteristics with the exosomes but have 100-fold higher production yield. Furthermore, the nanovesicles have natural targeting ability of cells by maintaining the topology of plasma membrane proteins. In vitro, chemotherapeutic drug-loaded nanovesicles induced TNF-α-stimulated endothelial cell death in a dose-dependent manner. In vivo, experiments in mice showed that the chemotherapeutic drug-loaded nanovesicles traffic to tumor tissue and reduce tumor growth without the adverse effects observed with equipotent free drug. Furthermore, compared with doxorubicin-loaded exosomes, doxorubicin-loaded nanovesicles showed similar in vivo antitumor activity. However, doxorubicin-loaded liposomes that did not carry targeting proteins were inefficient in reducing tumor growth. Importantly, removal of the plasma membrane proteins by trypsinization eliminated the therapeutic effects of the nanovesicles both in vitro and in vivo. Taken together, these studies suggest that the bioengineered nanovesicles can serve as novel exosome-mimetics to effectively deliver chemotherapeutics to treat malignant tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930532.V1
Abstract: Figure S5. Immunohistochemistry magenta of a) Immunohistochemistry magenta showing CCL21 and corresponding CCR7 expression within tumor biopsies for patient 1-013 and 3-009. b) Patient 1-013, a lymph node biopsy showing CD20, CD3 and CCL21 staining with serial sections. c) Patient 2-027, a liver met biopsy showing SOX10, CCR7, TK1 and PDL1 (DAB) within the same areas as shown in Fig 6.
Publisher: Springer Science and Business Media LLC
Date: 08-2005
DOI: 10.1038/NATURE03845
Publisher: Cold Spring Harbor Laboratory
Date: 21-08-2019
DOI: 10.1101/742023
Abstract: Uveal melanoma (UM) is a rare form of melanoma with a genetics and immunology that is different from skin melanoma. Previous studies have identified genetic driver events of early stage disease when the tumor is confined to the eye. However due to lack of a clinical rationale to biopsy metastatic disease, access to tumor material to perform molecular profiling of metastases has been limited. In this study, we have characterized genomic events in UM metastases using whole-genome sequencing of fresh frozen biopsies from thirty-two patients and profiled the transcriptomes of in idual tumor infiltrating lymphocytes in eight patients by single-cell sequencing. We find that 91% of the patients have metastases carrying inactivating events in the tumor suppressor BAP1 and this coincided with somatic alterations in GNAQ , GNA11 , CYSLTR2 , PLCB4 , SF3B1 and/or CDKN2A . Mutational signature analysis revealed a rare subset of tumors with prominent signs of UV damage, associated with outlier mutational burden. We study copy number variations (CNV) and find overrepresented events, some of which were not altered in matched primary eye tumors. A focused siRNA screen identified functionally significant genes of some of the segments recurrently gained. We reintroduced a functional copy of BAP1 into a patient-derived BAP1 deficient tumor cell line and found broad transcriptomic changes of genes associated with subtype distinction and prognosis in primary UM. Lastly, our analysis of the immune microenvironments of metastases revealed a presence of tumor-reactive T cells. However, a majority expressed the immune checkpoint receptors TIM-3, LAG3 and TIGIT, and to a lesser extent PD-1. These results provide an updated view of genomic events represented in metastatic UM and immune interactions in advanced lesions.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2020
DOI: 10.1038/S41467-020-15606-0
Abstract: Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma, and lacks effective treatments. Here we genomically profile metastatic tumors and infiltrating lymphocytes. BAP1 alterations are overrepresented and found in 29/32 of cases. Reintroducing a functional BAP1 allele into a deficient patient-derived cell line, reveals a broad shift towards a transcriptomic subtype previously associated with better prognosis of the primary disease. One outlier tumor has a high mutational burden associated with UV-damage. CDKN2A deletions also occur, which are rarely present in primaries. A focused knockdown screen is used to investigate overexpressed genes associated withcopy number gains. Tumor-infiltrating lymphocytes are in several cases found tumor-reactive, but expression of the immune checkpoint receptors TIM-3 , TIGIT and LAG3 is also abundant. This study represents the largest whole-genome analysis of uveal melanoma to date, and presents an updated view of the metastatic disease.
Publisher: Wiley
Date: 29-12-2009
DOI: 10.1111/J.1742-4658.2008.06790.X
Abstract: Susceptibility to cell death is a prerequisite for the elimination of tumour cells by cytotoxic immune cells, chemotherapy or irradiation. Activation of the death receptor Fas is critical for the regulation of immune cell homeostasis and efficient killing of tumour cells by apoptosis. To define the molecular changes that occur during selection for insensitivity to Fas-induced apoptosis, a resistant variant of the U937 cell line was established. In idual resistant clones were isolated and characterized. The most frequently observed defect in the resistant cells was reduced Fas expression, which correlated with decreased FAS transcription. Clones with such reduced Fas expression also displayed partial cross-resistance to tumour necrosis factor-alpha stimulation, but the mRNA expression of tumour necrosis factor receptors was not decreased. Reintroduction of Fas conferred susceptibility to Fas but not to tumour necrosis factor-alpha stimulation, suggesting that several alterations could be present in the clones. The reduced Fas expression could not be explained by mutations in the FAS coding sequence or promoter region, or by silencing through methylations. Protein kinase B and extracellular signal-regulated kinase, components of signalling pathways downstream of Ras, were shown to be activated in some of the resistant clones, but none of the three RAS genes was mutated, and experiments using chemical inhibitors could not establish that the activation of these proteins was the cause of Fas resistance as described in other systems. Taken together, the data illustrate that Fas resistance can be caused by reduced Fas expression, which is a result of an unidentified mode of regulation.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930523.V1
Abstract: Representativeness Table
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930508
Abstract: GSEA
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2023
DOI: 10.1200/JCO.22.01705
Abstract: About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking. In this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety. Ninety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively ( P .0001). The median PFS was 7.4 months versus 3.3 months ( P .0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months ( P .0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group. IHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930517.V1
Abstract: Patient s le information
Publisher: American Association for Cancer Research (AACR)
Date: 03-2010
DOI: 10.1158/1541-7786.MCR-09-0232
Abstract: The universal cyclin-dependent kinase inhibitor p27Kip1 functions as a tumor suppressor, and reduced levels of p27Kip1 connote poor prognosis in several human malignancies. p27Kip1 levels are predominately regulated by ubiquitin-mediated turnover of the protein, which is marked for destruction by the E3 ubiquitin ligase SCFSkp2 complex following its phosphorylation by the cyclin E–cyclin-dependent kinase 2 complex. Binding of phospho-p27Kip1 is directed by the Skp2 F-box protein, and this is greatly augmented by its allosteric regulator Cks1. We have established that programmed expression of c-Myc in the B cells of Eμ-Myc transgenic mice triggers p27Kip1 destruction by inducing Cks1, that this response controls Myc-driven proliferation, and that loss of Cks1 markedly delays Myc-induced lymphomagenesis and cancels the dissemination of these tumors. Here, we report that elevated levels of Skp2 are a characteristic of Eμ-Myc lymphomas and of human Burkitt lymphoma that bear MYC/Immunoglobulin chromosomal translocations. As expected, Myc-mediated suppression of p27Kip1 was abolished in Skp2-null Eμ-Myc B cells. However, the effect of Skp2 loss on Myc-driven proliferation and lymphomagenesis was surprisingly modest compared with the effects of Cks1 loss. Collectively, these findings suggest that Cks1 targets, in addition to p27Kip1, are critical for Myc-driven proliferation and tumorigenesis. Mol Cancer Res 8(3) 353–62
Publisher: American Chemical Society (ACS)
Date: 24-03-2016
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.ANNONC.2019.11.002
Abstract: The mouse strains usually used to generate patient-derived xenografts (PDXs) are immunocompromised, rendering them unsuitable for immunotherapy studies. Here we assessed the value of immune-PDX mouse models for predicting responses to anti-PD-1 checkpoint inhibitor therapy in patients. Melanoma biopsies contained in a retrospective biobank were transplanted into NOG mice or NOG mice expressing interleukin 2 (hIL2-NOG mice). Tumor growth was monitored, and comparisons were made with clinical data, sequencing data, and current in silico predictive tools. Biopsies grew readily in NOG mice but growth was heterogeneous in hIL2-NOG mice. IL2 appears to activate T-cell immunity in the biopsies to block tumor growth. Biopsy growth in hIL2-NOG mice was negatively associated with survival in patients previously treated with PD-1 checkpoint blockade. In two cases, the prospective clinical decisions of anti-PD-1 therapy or targeted BRAF/MEK inhibitors were supported by the observed responses in mice. Immune-PDX models represent a promising addition to future biomarker discovery studies and for clinical decision making in patients receiving immunotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745460.V1
Abstract: Follow up adverse events (AE) of grade ≥3 (n = 29 patients)
Publisher: Life Science Alliance, LLC
Date: 22-06-2020
Abstract: Chk1 kinase is downstream of the ATR kinase in the sensing of improper replication. Previous cell culture studies have demonstrated that Chk1 is essential for replication. Indeed, Chk1 inhibitors are efficacious against tumors with high-level replication stress such as Myc-induced lymphoma cells. Treatment with Chk1 inhibitors also combines well with certain chemotherapeutic drugs, and effects associate with the induction of DNA damage and reduction of Chk1 protein levels. Most studies of Chk1 function have relied on the use of inhibitors. Whether or not a mouse or cancer cells could survive if a kinase-dead form of Chk1 is expressed has not been investigated before. Here, we generate a mouse model that expresses a kinase-dead (D130A) allele in the mouse germ line. We find that this mouse is overtly normal and does not have problems with erythropoiesis with aging as previously been shown for a mouse expressing one null allele. However, similar to a null allele, homozygous kinase-dead mice cannot be generated, and timed pregnancies of heterozygous mice suggest lethality of homozygous blastocysts at around the time of implantation. By breeding the kinase-dead Chk1 mouse with a conditional allele, we are able to demonstrate that expression of only one kinase-dead allele, but no wild-type allele, of Chek1 is lethal for Myc-induced cancer cells. Finally, treatment of melanoma cells with tumor-infiltrating T cells or CAR-T cells is effective even if Chk1 is inhibited, suggesting that Chk1 inhibitors can be safely administered in patients where immunotherapy is an essential component of the arsenal against cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.C.6628509
Abstract: Purpose: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed. Patients and Methods: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for i BAP1 /i tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival. Results: Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival. Conclusions: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients. Significance: The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomarkers needing validation and become hypothesis generating for experimental research. /
Publisher: Frontiers Media SA
Date: 18-06-2018
Publisher: Cold Spring Harbor Laboratory
Date: 02-01-2020
DOI: 10.1101/2020.01.01.891739
Abstract: (1) BET bromodomain proteins regulate transcription by binding acetylated histones and attracting key factors for e.g. transcriptional elongation. BET inhibitors have been developed to block pathogenic processes such as cancer and inflammation. Despite having potent biological activities, BET inhibitors have still not made a breakthrough in clinical use for treating cancer. Multiple resistance mechanisms have been proposed but thus far no attempts to block this in glioma has been made. (2) Here, we have conducted a pharmacological synergy screen in glioma cells to search for possible combination treatments augmenting the apoptotic response to BET inhibitors. We first used HMBA, a compound that was developed as a differentiation therapy four decades ago but more recently was shown to primarily inhibit BET bromodomain proteins. Data was also generated using other BET inhibitors. (3) In the synergy screen, we discovered that several MEK inhibitors can enhance apoptosis in response to HMBA in rat and human glioma cells in vitro as well as in vivo xenografts. The combination is not unique to HMBA but also other BET inhibitors such as JQ1 and I-BET-762 can synergize with MEK inhibitors. (4) Our findings validate a combination therapy previously demonstrated to exhibit anti-cancer activities in multiple other tumor types but which appears to have been lost in translation to the clinic.
Publisher: Public Library of Science (PLoS)
Date: 18-05-2012
Publisher: Wiley
Date: 24-11-2017
DOI: 10.1111/BJH.14917
Abstract: Identifying and therapeutically targeting cancer cell liabilities is of utmost importance in order to improve the treatment of patients with malignancies of poor prognosis. The MYC family genes (MYC, MYCN and MYCL) are among the most deregulated proto-oncogenes in human cancer. Aberrant MYC expression is frequently associated with poor prognosis. Although many aspects of MYC-mediated tumour biology are well characterized, there are currently no effective means for targeting MYC in a specific manner that have been established for clinical use. This review first discusses the role of MYC in the pathogenesis of haematopoietic malignancies, and secondly summarizes how insight into MYC functions could be translated into therapeutic approaches. In particular, we will address the possibilities of taking advantage of MYC-induced cancer cell vulnerabilities that could be exploited in terms of synthetic lethal interactions.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2021
DOI: 10.1038/S41467-021-25332-W
Abstract: Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. We report the results of the PEMDAC phase 2 clinical trial ( n = 29 NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM). The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Objective responses and/or prolonged survival were seen in patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM. Trial registration ClinicalTrials.gov registration number: NCT02697630 (registered 3 March 2016). EudraCT registration number: 2016–002114-50.
Publisher: Elsevier BV
Date: 12-2016
Abstract: Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment. Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay. Thermal Proteome profiling, proteomics, cellular thermal shift assays, kinase and CEREP panel were used for target engagement, mode of action and selectivity investigations of MTH1 inhibitors. Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models. Here, we demonstrate that recently described MTH1 inhibitors, which fail to kill cancer cells, also fail to introduce the toxic oxidized nucleotides into DNA. We also describe a new MTH1 inhibitor TH1579, (Karonudib), an analogue of TH588, which is a potent, selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo. We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930520.V1
Abstract: Baseline characteristics, patient population
Publisher: Springer Science and Business Media LLC
Date: 08-12-2003
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.IMMUNI.2015.09.010
Abstract: Pattern-recognition receptors (PRRs) including Toll-like receptors, RIG-I-like receptors, and cytoplasmic DNA receptors are essential for protection against pathogens but require tight control to avert inflammatory diseases. The mechanisms underlying this strict regulation are unclear. MYSM1 was previously described as a key component of epigenetic signaling machinery. We found that in response to microbial stimuli, MYSM1 accumulated in the cytoplasm where it interacted with and inactivated TRAF3 and TRAF6 complexes to terminate PRR pathways for pro-inflammatory and type I interferon responses. Consequently, Mysm1 deficiency in mice resulted in hyper-inflammation and enhanced viral clearance but also susceptibility to septic shock. We identified two motifs in MYSM1 that were essential for innate immune suppression: the SWIRM domain that interacted with TRAF3 and TRAF6 and the metalloproteinase domain that removed K63 polyubiquitins. This study identifies MYSM1 as a key negative regulator of the innate immune system that guards against an overzealous self-destructive immune response.
Publisher: Informa UK Limited
Date: 15-07-2015
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930541.V1
Abstract: Figure S2. a) Gene signatures implicating short term survival. Statistical tests were carried out using DESeq2 and FDR-adjusted P-values were denoted with *, P 0.05 **, P 0.01 ***, P 0.001. b) Average of TK1 values assessed for all timepoints by the number of timepoints ided among response groups, PD, SD, PR. c) TK1 values in different response groups
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745463.V1
Abstract: Patient s le information
Publisher: Impact Journals, LLC
Date: 05-06-2011
Publisher: Informa UK Limited
Date: 02-2004
Publisher: Springer Science and Business Media LLC
Date: 02-04-2014
DOI: 10.1038/NATURE13181
Abstract: Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.BIOMATERIALS.2016.06.024
Abstract: To develop RNA-based therapeutics, it is crucial to create delivery vectors that transport the RNA molecule into the cell cytoplasm. Naturally released exosomes vesicles (also called "Extracellular Vesicles") have been proposed as possible RNAi carriers, but their yield is relatively small in any cell culture system. We have previously generated exosome-mimetic nanovesicles (NV) by serial extrusions of cells through nano-sized filters, which results in 100-times higher yield of extracellular vesicles. We here test 1) whether NV can be loaded with siRNA exogenously and endogenously, 2) whether the siRNA-loaded NV are taken up by recipient cells, and 3) whether the siRNA can induce functional knock-down responses in recipient cells. A siRNA against GFP was first loaded into NV by electroporation, or a c-Myc shRNA was expressed inside of the cells. The NV were efficiently loaded with siRNA with both techniques, were taken up by recipient cells, which resulted in attenuation of target gene expression. In conclusion, our study suggests that exosome-mimetic nanovesicles can be a platform for RNAi delivery to cell cytoplasm.
Publisher: Impact Journals, LLC
Date: 18-03-2016
Publisher: Springer Science and Business Media LLC
Date: 10-08-2017
Abstract: Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo , apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2019
Publisher: American Association for Cancer Research (AACR)
Date: 14-11-2011
DOI: 10.1158/1078-0432.CCR-11-1198
Abstract: Purpose: The transcription factor c-Myc (or “Myc”) is a master regulator of pathways driving cell growth and proliferation. MYC is deregulated in many human cancers, making its downstream target genes attractive candidates for drug development. We report the unexpected finding that B-cell lymphomas from mice and patients exhibit a striking correlation between high levels of Myc and checkpoint kinase 1 (Chk1). Experimental Design: By in vitro cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of Chk1 in Myc-overexpressing cells. Results: We show that Myc indirectly induces Chek1 transcript and protein expression, independently of DNA damage response proteins such as ATM and p53. Importantly, we show that inhibition of Chk1, by either RNA interference or a novel highly selective small molecule inhibitor, results in caspase-dependent apoptosis that affects Myc-overexpressing cells in both in vitro and in vivo mouse models of B-cell lymphoma. Conclusion: Our data suggest that Chk1 inhibitors should be further evaluated as potential drugs against Myc-driven malignancies such as certain B-cell lymphoma/leukemia, neuroblastoma, and some breast and lung cancers. Clin Cancer Res 17(22) 7067–79. ©2011 AACR.
Publisher: MDPI AG
Date: 26-08-2021
Abstract: Traditionally, immune evasion and immunotherapy have been studied in cancers with a high mutational load such as melanoma or lung cancer. In contrast, small intestinal neuroendocrine tumours (SINETs) present a low frequency of somatic mutations and are described as genetically stable tumours, rendering immunotherapies largely unchartered waters for SINET patients. SINETs frequently metastasise to the regional lymph nodes and liver at the time of diagnosis, and no curative treatments are currently available for patients with disseminated disease. Here, we characterised the immune landscape of SINET and demonstrated that tumour-infiltrating lymphocytes (TILs) can be expanded and activated during autologous tumour challenge. The composition of lymphocyte subsets was determined by immunophenotyping of the SINET microenvironment in one hepatic and six lymph node metastases. TILs from these metastases were successfully grown out, enabling immunophenotyping and assessment of PD-1 expression. Expansion of the TILs and exposure to autologous tumour cells in vitro resulted in increased T lymphocyte degranulation. This study provides insights into the largely unknown SINET immune landscape and reveals the anti-tumour reactivity of TILs, which might merit adoptive T cell transfer as a feasible treatment option for patients with SINET.
Publisher: Impact Journals, LLC
Date: 08-09-2014
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.C.6628509.V2
Abstract: Purpose: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed. Patients and Methods: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for i BAP1 /i tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival. Results: Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival. Conclusions: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients. Significance: The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomarkers needing validation and become hypothesis generating for experimental research. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.C.6628509.V1
Abstract: Abstract Purpose: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed. Patients and Methods: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the HDAC inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for BAP1 tumor suppressor gene. Here we present the two-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival. Results: Durable responses were observed in four patients, with additional eight patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared to those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival. Conclusions: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients. /
Publisher: BMJ
Date: 30-01-2020
DOI: 10.1136/GUTJNL-2018-317856
Abstract: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC lifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies. We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC. We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.
Publisher: MDPI AG
Date: 10-06-2022
Abstract: The ersity of T cells in the human liver may reflect the composition of TILs in CRLM. Our ex vivo characterization of CRLM vs. adjacent liver tissue detected CD103+CD39+CD8+ TRM cells predominantly in CRLM, which prompted further assessments. These TRM cells responded to cognate antigens in vitro. As functional activities of autologous TILs are central to the implementation of personalized cancer treatments, we applied a patient-derived xenograft (PDX) model to monitor TILs’ capacity to control CRLM-derived tumors in vivo. We established PDX mice with CRLMs from two patients, and in vitro expansion of their respective TILs resulted in opposing CD4+ vs. CD8+ TIL ratios. These CRLMs also displayed mutated KRAS, which enabled trametinib-mediated inhibition of MEK. Regardless of the TIL subset ratio, persistent or transient control of CRLM-derived tumors of limited size by the transferred TILs was observed only after trametinib treatment. Of note, a portion of transferred TILs was observed as CD103+CD8+ TRM cells that strictly accumulated within the autologous CRLM-derived tumor rather than in the spleen or blood. Thus, the predominance of CD103+CD39+CD8+ TRM cells in CRLM relative to the adjacent liver and the propensity of CD103+CD8+ TRM cells to repopulate the autologous tumor may identify these TILs as strategic targets for therapies against advanced CRC.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930523
Abstract: Representativeness Table
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930544.V1
Abstract: Figure S1. a) Time To Response (TTR) according to RECIST 1.1. b) Duration of Response (DOR) according to RECIST 1.1. c) Quality of life assessments: Boxplot of EQ-5D VAS evaluation, screening and last known assessment at database lock. d) EQ-5D VAS, change from screening to last known assessment. e) The functional Assessment of Cancer Therapy – General (FACT-G) score sub-scales at screening and at last known assessments
Publisher: Elsevier BV
Date: 11-2021
Publisher: Cambridge University Press (CUP)
Date: 10-2003
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930529
Abstract: Figure S6. Analysis of clinical parameters gender (a), tumor BAP1 status (b) and LDH levels (c-d) compared to serum levels of CCL21 (a-c) or presence of TLS-like regions in tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745487
Abstract: Figure S1. a) Time To Response (TTR) according to RECIST 1.1. b) Duration of Response (DOR) according to RECIST 1.1. c) Quality of life assessments: Boxplot of EQ-5D VAS evaluation, screening and last known assessment at database lock. d) EQ-5D VAS, change from screening to last known assessment. e) The functional Assessment of Cancer Therapy – General (FACT-G) score sub-scales at screening and at last known assessments
Publisher: American Association for Cancer Research (AACR)
Date: 20-05-2013
DOI: 10.1158/2767-9764.22930520
Abstract: Baseline characteristics, patient population
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745484
Abstract: Figure S2. a) Gene signatures implicating short term survival. Statistical tests were carried out using DESeq2 and FDR-adjusted P-values were denoted with *, P 0.05 **, P 0.01 ***, P 0.001. b) Average of TK1 values assessed for all timepoints by the number of timepoints ided among response groups, PD, SD, PR. c) TK1 values in different response groups
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745457.V1
Abstract: Complete differential expression results
Publisher: Informa UK Limited
Date: 09-2008
DOI: 10.1128/MCB.00907-07
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930547.V1
Abstract: IHC magenta showing low mag of CD20 varied staining of TLS-like (borderline-tertiary lymphoid structures) followed by high magnification images of CD20, CD3, CCL21 within serial sections for Pt 2-027 ( b A /b ), 3-010 ( b B /b ). Also see a href="#SMF5" target="_blank" Supplementary Fig. S5 /a . Low and high magnification images of CD20 sup + /sup TLS-like staining for Pt. 2-026 ( b C /b ) and no TLS s le Pt. 4-017 ( b D /b ). Kaplan–Meier analysis showing PFS ( b E /b ) and OS ( b F /b ), respectively iding patient population into two groups based on IHC, no-TLS ( i n /i = 4) and TLS-like ( i n /i = 18). Also see a href="#SMF5" target="_blank" Supplementary Fig. S5 /a . b G, /b Heatmap showing top 10% genes with highest log sub /sub fold change, among all positively and negatively significantly regulated genes comparing no-TLS and TLS-like groups using bulk RNA-seq (log sub /sub Reads Per Kilobase per Million mapped reads [RPKM] normalized values). Arrows represent relevant TLS-based gene signatures. Genes with FDR-adjusted i P /i values .05 were considered statistically significant. b H, /b In idual box plots showing i CCL19 /i , i CCL21 /i , i CCR7 /i , and i CD79A /i changes in expression between the groups. Statistical tests were carried out using DESeq2 and FDR-adjusted i P /i values were denoted with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2017
Publisher: Informa UK Limited
Date: 15-10-2011
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.ULTRAMIC.2010.06.010
Abstract: Atomic force microscopy (AFM) holds great potential for studying the nanoscale surface structures of living cells, and to measure their interactions with abiotic surfaces, other cells, or specific biomolecules. However, the application of AFM in microbiology is challenging due to the difficulty of immobilising bacterial cells to a flat surface without changing the cell surface properties or cell viability. We have performed an extensive and thorough study of how to functionalise surfaces in order to immobilise living bacteria for AFM studies in liquid environments. Our aim was to develop a scheme which allows bacterial cells to be immobilised to a flat surface with sufficient strength to avoid detachment during the AFM scanning, and without affecting cell surface chemistry, structure, and viability. We compare and evaluate published methods, and present a new, reproducible, and generally applicable scheme for immobilising bacteria cells for an AFM imaging. Bacterial cells were immobilised to modified glass surfaces by physical confinement of cells in microwells, physisorption to positively charged surfaces, covalent binding to amine- or carboxyl-terminated surfaces, and adsorption to surfaces coated with highly adhesive polyphenolic proteins originating from the mussel Mytilus edulis. Living cells could be immobilised with all of these approaches, but many cells detached when immobilised by electrostatic interactions and imaged in buffers like PBS or MOPS. Cells were more firmly attached when immobilised by covalent binding, although some cells still detached during AFM imaging. The most successful method revealed was immobilisation by polyphenolic proteins, which facilitated firm immobilisation of the cells. Furthermore, the cell viability was not affected by this immobilisation scheme, and adhesive proteins thus provide a fast, reproducible, and generally applicable scheme for immobilising living bacteria for an AFM imaging.
Publisher: Elsevier BV
Date: 05-2005
DOI: 10.1016/J.CCR.2005.03.036
Abstract: Checkpoints that control Myc-mediated proliferation and apoptosis are bypassed during tumorigenesis. Genes encoding polyamine biosynthetic enzymes are overexpressed in B cells from E mu-Myc transgenic mice. Here, we report that disabling one of these Myc targets, Ornithine decarboxylase (Odc), abolishes Myc-induced suppression of the Cdk inhibitors p21(Cip1) and p27(Kip1), thereby impairing Myc's proliferative, but not apoptotic, response. Moreover, lymphoma development was markedly delayed in E mu-Myc Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine (DFMO). Strikingly, tumors ultimately arising in E mu-Myc Odc(+/-) transgenics lacked deletions of Arf, suggesting that targeting Odc forces other routes of transformation. Therefore, Odc is a critical Myc transcription target that regulates checkpoints that guard against tumorigenesis and is an effective target for cancer chemoprevention.
Publisher: Proceedings of the National Academy of Sciences
Date: 06-07-2017
Abstract: The development of BRAF inhibitors is a notable clinical success, leading to rapid initial melanoma regression. However, response rates are tempered by a short duration of response in a majority of patients. This study has determined the effects of BRAF inhibition on mutant melanoma cells, as well as on the RNA contents in their vesicular secretome. Our data show the presence of miR-211–5p in all extracellular vesicular (EV) subsets upon treatment with BRAF inhibitors, which provides a fundamental starting point to understand the regulatory effects of molecules present in EVs, which may have implications for disease progression in patients receiving BRAF-targeted treatment.
Publisher: American Chemical Society (ACS)
Date: 18-09-2009
DOI: 10.1021/BM900589R
Abstract: We utilize an aqueous extract of fish proteins (FPs) as a coating for minimizing the adsorption of fibrinogen (Fg) and human serum albumin (HSA). The surfaces include stainless steel (SS), gold (Au), silicon dioxide (SiO(2)), and poly(styrene) (PS). The adsorption processes (kinetics and adsorbed mass) are followed by quartz crystal microbalance with dissipation (QCM-D). Complementary surface information is provided by X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). QCM-D shows no mass increases to any of the FP-coated surfaces upon treating with Fg or HSA. Also, when Fg- or HSA-coated surfaces are exposed to the FPs, a significant increase in adsorbed mass occurs because the FPs are highly surface-active displacing Fg. Additionally, fluorescence microscopy confirms that very little Fg adsorbs to the FP-coated surfaces. We propose that FP coatings prevent protein adsorption by steric stabilization and could be an alternative method for preventing unwanted bioadhesion on medical materials.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930514
Abstract: Follow up adverse events (AE) of grade ≥3 (n = 29 patients)
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930517
Abstract: Patient s le information
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930514.V1
Abstract: Follow up adverse events (AE) of grade ≥3 (n = 29 patients)
Publisher: Informa UK Limited
Date: 12-2020
DOI: 10.2147/CLEP.S267583
Publisher: Springer Science and Business Media LLC
Date: 06-06-2005
Abstract: Rel/NF-kappaB transcription factors are critical arbiters of immune responses, cell survival, and transformation, and are frequently deregulated in cancer. The p50 NF-kappaB 1 component of Rel/NF-kappaB DNA-binding dimers regulates genes involved in both cell cycle traverse and apoptosis. Nfkb 1 loss accelerates B cell growth and leads to increased B cell turnover in vivo, phenotypes akin to those manifested in B cells of Emu-Myc transgenic mice, a model of human Burkitt lymphoma. Interestingly, Emu-Myc B cells express reduced levels of cytoplasmic and nuclear NF-kappaB 1 and have reduced Rel/NF-kappaB DNA-binding activity, suggesting that Myc-mediated repression of NF-kappaB 1 might mediate its proliferative and apoptotic effects on B cells. Furthermore, Nfkb 1 expression was reduced in the majority of Emu-Myc lymphomas and was also suppressed in human Burkitt lymphoma. Nonetheless, loss of Nfkb 1 did not appreciably affect Myc's proliferative or apoptotic responses in B cells and had no effect on lymphoma development in Emu-Myc mice. Therefore, Nfkb 1 is dispensable for Myc-induced lymphomagenesis..
Publisher: Portland Press Ltd.
Date: 20-03-2007
DOI: 10.1042/BST0350305
Abstract: The Myc oncogenes are dysregulated in 70% of human cancers. They encode transcription factors that bind to E-box sequences in DNA, driving the expression of a vast amount of target genes. The biological outcome is enhanced proliferation (which is counteracted by apoptosis), angiogenesis and cancer. Based on the biological effects of Myc overexpression it was originally assumed that the important Myc target genes are those encoding components of the cell cycle machinery. Recent work has challenged this notion and indicates that Myc target genes encoding metabolic enzymes deserve attention, as they may be critical arbiters of Myc in cancer. Thus targeting metabolic enzymes encoded by Myc-target genes may provide a new means to treat cancer that have arisen in response to deregulated Myc oncogenes.
Publisher: IOP Publishing
Date: 04-2011
DOI: 10.1088/0957-4484/22/22/225601
Abstract: We report a simple, rapid and cost-effective method based on evaporation induced assembly to grow 3D binary colloidal assemblies on a hydrophobic/hydrophilic substrate by simple drop casting. The evaporation of a mixed colloidal drop results in ring-like or uniform area deposition depending on the concentration of particles, and thus assembly occurs at the periphery of a ring or uniformly all over the drop area. Binary colloidal assemblies of different crystal structure are successfully prepared over a wide range of size ratios (γ = small/large) from 0.06 to 0.30 by tuning the γ of the micro- and nanoparticles used during assembly. The growth mechanism of 3D binary colloidal assemblies is investigated and it is found that electrostatic forces facilitate assembly formation until the end of the evaporation process, with capillary forces also playing a role. In addition, the effects of solvent type, humidity, and salt concentration on crystal formation and ordering behaviour are also examined. Furthermore, long range, highly ordered binary colloidal assemblies can be fabricated by the choice of a low conducting solvent combined with evaporation induced assembly.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930511
Abstract: Complete differential expression results
Publisher: American Society of Hematology
Date: 25-09-2014
DOI: 10.1182/BLOOD-2014-06-584524
Abstract: The Myc oncoprotein targets central regulators of the SUMOylation machinery, resulting in a hyper-SUMOylation state in Myc-induced lymphoma. Targeting SUMOylation by genetic or pharmacologic means represents a novel therapeutic option for lymphomas with MYC involvement.
Publisher: Wiley
Date: 04-02-2011
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745454.V1
Abstract: GSEA
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930553.V1
Abstract: Kaplan–Meier analysis showing. PFS ( b A /b ) and OS ( b B /b ), respectively using pretreatment plasma CCL21 (pg/mL) measurements based on their median values. b C, /b Correlation between CCL21 (pg/mL) and CD3 sup + /sup CCR7 sup + /sup CD45RA sup + /sup (% counts) matched patient s les ( i n /i = 23). b D, /b Flow cytometry–based comparison between short- and long-term survivors for CD3 sup + /sup CCR7 sup + /sup CD45RA sup + /sup % (T naïve and T stem cell memory) analysis using pretreatment blood s les ( i n /i = 24). Statistical test was unpaired two-tailed i t /i tests, assuming equal variance. b E, /b Kaplan–Meier analysis showing OS using median CD3 sup + /sup CCR7 sup + /sup CD45RA sup + /sup % values.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930508.V1
Abstract: GSEA
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.CRC-22-0490
Abstract: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed. We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for BAP1 tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival. Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival. This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients. The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomarkers needing validation and become hypothesis generating for experimental research.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930511.V1
Abstract: Complete differential expression results
Publisher: Springer Science and Business Media LLC
Date: 25-01-2016
DOI: 10.1038/ONC.2015.521
Abstract: Inhibiting the bromodomain and extra-terminal (BET) domain family of epigenetic reader proteins has been shown to have potent anti-tumoral activity, which is commonly attributed to suppression of transcription. In this study, we show that two structurally distinct BET inhibitors (BETi) interfere with replication and cell cycle progression of murine Myc-induced lymphoma cells at sub-lethal concentrations when the transcriptome remains largely unaltered. This inhibition of replication coincides with a DNA-damage response and enhanced sensitivity to inhibitors of the upstream replication stress sensor ATR in vitro and in mouse models of B-cell lymphoma. Mechanistically, ATR and BETi combination therapy cause robust transcriptional changes of genes involved in cell death, senescence-associated secretory pathway, NFkB signaling and ER stress. Our data reveal that BETi can potentiate the cell stress and death caused by ATR inhibitors. This suggests that ATRi can be used in combination therapies of lymphomas without the use of genotoxic drugs.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2019
Location: United States of America
No related grants have been discovered for Jonas Nilsson.